Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma

Abstract

SummaryThe genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ~3500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (KDM6A)1, JARID1C (KDM5C) and SETD22. These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control3. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodeling complex gene PBRM14 as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.

Whole exome sequencing of adenoid cystic carcinoma

“…Somatic mutations have been reported in ARID1A in clear cell ovarian, renal (ccRCC), transitional cell bladder (TCC) and gastric carcinoma (3,(11)(12)(13), CREBBP and EP300 in non-Hodgkin lymphoma (NHL) (14), and KDM6A (UTX) in ccRCC and TCC (3,11). Each of these genes had only truncating mutations identified, with the exception of a truncating and missense mutation in CREBBP.…”

“…Twenty-three pretreatment primary ACC specimens, 1 localregional lymph node metastasis (Supplemental Table 1; supplemental material available online with this article; doi:10.1172/ JCI67201DS1), and corresponding matching normal salivary gland parenchymal samples were subjected to solution phase capture and next-generation sequencing of the coding exome as well as evaluation for and validation of somatic mutations as previously described (3). The case series consisted of 19 that were scored as positive for MYB activation and comprised a roughly equal mixture of cribriform and predominantly solid histological forms of ACC (Supplemental Table 1).…”

Reliable detection of subclonal single-nucleotide variants in tumour cell populations

“…The control sample allows for estimating the local error rate, which increases the power for calling true variants at a given false-positive rate. Unlike true variants, sequencing errors depend on the directionality of sequencing and tend to occur more often on one DNA strand than the other, which can be used to further increase the specificity of variant calling 14,15 . Batch-library preparation and sequencing in the same run ensure identical noise characteristics of test and control, an important prerequisite for reliable variant detection.…”

Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

“…On the other hand, aberrations of none of the 3,662 genes listed in Supporting Information Table S4 showed a difference in incidence of 10% or more between our cohort and the COSMIC data; the genetic aberration profiles in our cohort were generally consistent with those for the COSMIC data. Supporting Information Table S5 compares in more detail the genetic aberration profiles of the well‐known VHL 29 and PBRM1 30 genes in the initial cohort with those in the COSMIC data. Multiple non‐synonymous single‐nucleotide mutations and/or indels were again shared between our cohort and the COSMIC data, thus confirming the reliability of our whole‐exome analysis.…”